Abstract Obesity is the leading cause of non-alcoholic fatty liver disease (NAFLD) and type II diabetes. Both of these conditions contribute to the morbidity and mortality rates of obesity. Large population studies have demonstrated a negative correlation between serum bilirubin levels and the development of NAFLD and type II diabetes. Despite these correlative studies, the mechanism by which bilirubin protects against NAFLD and type II diabetes is not known. We have exciting data demonstrating for the first time that bilirubin is also a signaling molecule capable of signaling through the nuclear hormone receptors such as peroxisome proliferator- activated receptor (PPAR?) In addition, bilirubin can also inactivate glycogen synthase kinase-3? (GSK3?) to increase PPAR? target genes such as fibroblast growth factor 21 (FGF21); however, the specific role of GSK3? inactivation/PPAR? activation to the anti-steatotic and anti-diabetic actions of moderate hyperbilirubinemia is not known. Biliverdin reductase (BVR) is the enzyme responsible for the reduction of biliverdin to bilirubin. It can generate bilirubin that is found in the plasma as well as bilirubin generated inside the cell. The goal of this proposal is to test the central hypothesis that bilirubin and BVRA protect against obesity induced hepatic steatosis and insulin resistance via activation of the PPAR??signaling axis. Aim 1 of the proposal will test the hypothesis that chronic moderate hyperbilirubinemia resulting from bilirubin treatment or antagonism of hepatic UGT1A1 can reverse dietary obesity induced hepatic steatosis and hepatic insulin resistance. Aim 2 of the proposal will test the hypothesis that moderate hyperbilirubinemia reverses hepatic steatosis and insulin resistance via activation of PPAR?. Aim 3 of the proposal will test the hypothesis that that specific loss of hepatic bilirubin generation enhances hepatic steatosis and insulin resistance through a GSK3??mediated pathway that decreases PPAR? activity. Findings of the studies outlined in the proposal will have profound implications on the development of moderate hyperbilirubinemia as a novel therapy for the treatment of obesity induced NAFLD and insulin resistance. These studies will also determine the novel role of bilirubin as a nuclear hormone receptor signaling molecule and the role of this mechanism in the protection against obesity induced NAFLD and insulin resistance.